Stress increases addictive behaviors. Corticotropin-releasing factor (CRF) is released in the ventral tegmental area (VTA) during stressful events, and produces relapse to cocaine seeking. However, the mechanism by which CRF produces stress-dependent relapse to cocaine seeking is poorly understood. The main goal of this proposal is to understand the role of CRF-R1 and CRF-R2, and the CRF-BP in the VTA in modulating dopamine release and stress-induced relapse to cocaine seeking. Over the past four years, my laboratory has collected evidence showing that CRF activates CRF-R2 to increase NMDAR-mediated currents in VTA DA neurons. Furthermore, we have evidence that CRF-R1 activation in VTA DA neurons increases firing activity via activation of Ih. By performing patch-clamp recordings in the VTA, specific aim 1 will elucidate in detail: a) the intracellular pathway responsible for the CRFR1-dependent increase in firing rate, and b) the intracellular pathways responsible for the CRF-R2-dependent increase in NMDAR currents in the VTA. Specific aim 2 will determine the role of CRF-R1 and CRF-R2 in modulating DA release in the ventral striatum. Specific aim 3 will determine the role of CRF-R1- and CRF-R2-dependent pathways in inhibiting footshock- induced relapse to cocaine seeking. Finally, specific aim 4 will take a deep mechanistic look at the CRF-BP. The results from this grant will produced a deep mechanistic and behavioral understanding of the various effects of CRF on VTA neurons. Our results will likely create new therapeutic leads toward agents that disrupt the CRF-R1- and CRF- R2-dependent effects on VTA neurons and thus stress-induced cocaine seeking. PUBLIC HEALTH RELEVANCE: Stress increases addictive behavior. However, the mechanism by which stress-released molecules exert their negative effects on drug-seeking are poorly understood. The main goal of this project is to elucidate the role of CRFR1 and CRFR2 in promoting stress-enhanced relapse to cocaine seeking. Relapse to drug seeking is a major health problem that still has no cure. The results from this proposal could enable us to create new therapeutic targets aimed at inhibiting the ability of stressful event to increase relapse to substance abuse.